Abstract

Altered regulation of signaling pathways can lead to pathologies including cardiac hypertrophy and heart failure. We report that neonatal and adult cardiomyocytes express chromogranin B (CGB), a Ca 2+ binding protein that modulates Ca 2+ release by the inositol 1,4,5-trisphosphate receptor (InsP 3R). Using fluorescent Ca 2+ indicator dyes, we found that CGB regulates InsP 3-dependent Ca 2+ release in response to angiotensin II, an octapeptide hormone that promotes cardiac hypertrophy. ELISA experiments and luciferase reporter assays identified angiotensin II as a potent inducer of brain natriuretic peptide (BNP), a hormone that recently emerged as an important biomarker in cardiovascular disease. CGB was found to regulate angiotensin II-stimulated and basal secretion, expression and promoter activity of BNP that depend on the InsP 3R. Moreover, we provide evidence that CGB acts via the transcription activity of nuclear factor KB in an InsP 3/Ca 2+-dependent manner but independent of nuclear factor of activated T cells. In vivo experiments further showed that cardiac hypertrophy induced by angiotensin II, a condition characterized by increased ventricular BNP production, is associated with upregulation of ventricular CGB expression. Overexpression of CGB in cardiomyocytes, in turn, induced the BNP promoter. The evidence presented in this study identifies CGB as a novel regulator of cardiomyocyte InsP 3/Ca 2+-dependent signaling, nuclear factor κB activity, and BNP production © 2008 American Heart Association, Inc.